Mild overexpression of MeCP2 causes a progressive neurological disorder in mice

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of M...

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Bibliographic Details
Published in:Human molecular genetics 2004-11, Vol.13 (21), p.2679-2689
Main Authors: Collins, Ann L., Levenson, Jonathan M., Vilaythong, Alexander P., Richman, Ronald, Armstrong, Dawna L., Noebels, Jeffrey L., David Sweatt, J., Zoghbi, Huda Y.
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal
Biological and medical sciences
Blotting, Western
Chromosomal Proteins, Non-Histone - metabolism
Disease Models, Animal
DNA-Binding Proteins - metabolism
Electroencephalography
Electrophysiology
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Developmental
Genetics of eukaryotes. Biological and molecular evolution
Humans
Immunohistochemistry
Methyl-CpG-Binding Protein 2
Mice
Mice, Transgenic
Molecular and cellular biology
Mutation
Nervous System Diseases - genetics
Nervous System Diseases - pathology
Repressor Proteins - metabolism
Rett Syndrome - genetics
Time Factors
X Chromosome
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Summary:Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2Tg1, which expresses MeCP2 at ∼2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and ∼30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddh282